IDH1 and IDH2 Mutations in Acute Myeloid Leukemia

by Kamran Mirza MBBS PhD FCAP

April 5, 2026

If your bone marrow or molecular test report mentions an IDH1 mutation or an IDH2 mutation, these refer to changes in two closely related genes that affect how leukemia cells process energy — and, as a result, how they grow and mature. IDH1 and IDH2 mutations are found in approximately 20% of adults with acute myeloid leukemia (AML) and are important for two reasons: they carry prognostic information and identify patients eligible for a specific group of targeted drugs called IDH inhibitors. These drugs work through a mechanism quite different from standard chemotherapy — rather than killing leukemia cells outright, they remove a chemical block that has been stopping the cells from growing into normal blood cells. This article explains what IDH mutations are, how they cause disease, and what a positive result means for treatment.

What the test looks for

The IDH1 and IDH2 genes provide instructions for making enzymes — proteins that carry out specific chemical reactions inside cells. The normal IDH1 and IDH2 enzymes are part of the cell’s energy-processing machinery. They convert one chemical into another as part of the normal process by which cells generate energy from nutrients.

When either gene is mutated, the enzyme it encodes produces an effect it should not have. Instead of carrying out its normal reaction, the mutated enzyme produces an abnormal chemical called 2-hydroxyglutarate — often referred to as 2-HG. In normal cells, 2-HG is not produced or is produced only in tiny amounts. In leukemia cells with an IDH mutation, 2-HG builds up to high levels.

2-HG acts like a chemical jammer. It interferes with a group of enzymes inside the cell that control which genes are switched on and off. In particular, it blocks enzymes that help blood-forming cells mature — the process by which an immature blast cell gradually develops into a working red blood cell, white blood cell, or platelet. With this maturation process blocked, the blasts stay stuck in an immature, abnormal state. They keep dividing but never grow up, and over time, they crowd out the healthy blood cells that the bone marrow should be producing.

This is what makes IDH mutations unusual compared to other AML-driving mutations. Most other AML mutations — such as FLT3 — work by switching on a growth signal that tells cells to multiply too fast. IDH mutations work differently: they jam the maturation process, leaving cells trapped at an early stage of development. This distinction matters because it underpins how IDH inhibitor drugs work.

IDH1 versus IDH2

IDH1 and IDH2 are different genes that encode slightly different versions of the same enzyme. IDH1 works inside the main fluid-filled space of the cell (the cytoplasm), while IDH2 works inside the cell’s energy-generating structures (the mitochondria). Both produce 2-HG when mutated, and both cause the same downstream jamming of blood cell maturation — but different drugs target them.

IDH1 mutations are found in approximately 6–10% of AML cases. The most common specific mutation is called IDH1 R132, referring to a change at position 132 of the IDH1 protein.

IDH2 mutations are found in approximately 8–13% of AML cases. The most common specific mutations are IDH2 R140 and IDH2 R172, referring to changes at positions 140 and 172 of the IDH2 protein. These two IDH2 mutation types have somewhat different implications — R140 mutations tend to co-occur with NPM1 mutations and carry an intermediate prognosis. In contrast, R172 mutations are less common and carry a somewhat less favorable outlook.

Both IDH1 and IDH2 mutations are somatic — meaning they develop in a leukemia cell during a person’s lifetime and are not inherited. They are not passed to children and do not carry hereditary implications for family members.

Why is the test done

IDH1 and IDH2 testing are performed as part of the standard molecular workup for all newly diagnosed AML cases. The result serves three purposes: helping classify the AML subtype and assess risk, identifying patients eligible for targeted IDH inhibitor therapy, and providing a molecular marker that can be tracked during treatment to detect any residual leukemia.

IDH mutations are also tested at the time of relapse. Like FLT3 mutations, IDH mutation status can change between diagnosis and relapse — a mutation present at diagnosis may disappear, and a new one may appear. Testing at relapse ensures that the treatment plan is based on the cancer’s current biology.

How the test is performed

IDH1 and IDH2 mutations are detected from a bone marrow sample, or occasionally from a blood sample when large numbers of leukemia blasts are circulating in the blood. DNA is extracted from the leukemia cells and analyzed in the laboratory.

The most common approach is next-generation sequencing (NGS) — a technology that reads the genetic code across many genes at once. NGS can detect IDH1 and IDH2 mutations alongside FLT3, NPM1, TP53, and dozens of other clinically relevant changes in a single test. This comprehensive approach is valuable because the full combination of mutations present — not just IDH status alone — determines AML risk classification and the overall treatment plan.

Targeted molecular testing using PCR-based methods can also quickly detect the most common IDH1 and IDH2 mutations and may be used alongside NGS at some centers for faster turnaround.

How results are reported

IDH results are reported as “mutation detected” or “not detected” for each gene separately. When a mutation is found, the report will describe the specific change — for example, IDH1 p.R132H or IDH2 p.R140Q. The notation describes the exact amino acid change in the protein.

The variant allele frequency (VAF) — the proportion of tested cells carrying the mutation — is usually included. A high VAF suggests that most leukemia cells carry the IDH mutation. A low VAF may indicate that only a portion of the leukemia carries it, or that the mutation was detected in a small residual population after treatment.

Because IDH mutations can serve as markers of residual leukemia after treatment, the same mutation identified at diagnosis will be tracked in follow-up molecular tests. A falling VAF during treatment is a sign that the IDH inhibitor or chemotherapy is working; a rising VAF after remission may signal early relapse.

What the result means

IDH1 mutation detected

An IDH1 mutation means the leukemia cells produce 2-HG through the IDH1 enzyme, and that their maturation is chemically blocked. In terms of prognosis, IDH1 mutations in AML are generally associated with an intermediate risk — neither the most favorable nor the most aggressive end of the spectrum. The prognostic picture is significantly shaped by the presence of other mutations alongside IDH1. For example, IDH1 mutations that co-occur with an NPM1 mutation and without a high-burden FLT3-ITD mutation tend to fall into a more favorable category.

An IDH1 mutation makes the leukemia eligible for treatment with ivosidenib (Tibsovo), an IDH1 inhibitor. Ivosidenib works by fitting into the mutated IDH1 enzyme and blocking it from producing 2-HG. With 2-HG production stopped, the chemical jam on blood cell maturation is lifted, and leukemia cells can, in many cases, finish maturing into normal blood cells. This process is called differentiation therapy.

Ivosidenib is approved for newly diagnosed IDH1-mutated AML in patients who are not fit for intensive chemotherapy, and for relapsed or treatment-resistant IDH1-mutated AML. It can also be used in combination with standard chemotherapy (azacitidine) in newly diagnosed patients. In the AG120-C-001 trial of patients with relapsed or refractory IDH1-mutated AML, ivosidenib achieved an overall response rate of approximately 41%, with complete responses or complete responses with partial haematologic recovery in approximately 22% of patients — meaningful results in a setting where treatment options are limited.

IDH2 mutation detected

An IDH2 mutation means the leukemia cells are producing 2-HG through the IDH2 enzyme, also blocking blood cell maturation. The prognostic significance depends on which specific IDH2 mutation is present. IDH2 R140 mutations frequently co-occur with NPM1 mutations and tend to carry an intermediate prognosis. IDH2 R172 mutations are less common and are generally associated with a less favorable prognosis, particularly when they occur in the absence of other favorable mutations.

An IDH2 mutation makes the leukemia eligible for treatment with IDH2 inhibitors. Two are currently approved:

Enasidenib (Idhifa). The first IDH2 inhibitor approved for AML. It works by blocking the mutated IDH2 enzyme, reducing 2-HG levels, and allowing leukemia cells to begin differentiating. Enasidenib is approved for relapsed or treatment-resistant IDH2-mutated AML. In the AG221-C-001 trial, enasidenib achieved an overall response rate of approximately 40% in this setting, with a median overall survival of approximately 9.3 months — a meaningful improvement in a group with few effective options. Enasidenib is active against both R140 and R172 IDH2 mutations.
Olutasidenib (Rezlidhia). A newer, more selective IDH1 inhibitor — though note that olutasidenib targets IDH1, not IDH2. It is approved for relapsed or refractory IDH1-mutated AML and provides an alternative to ivosidenib in that setting, with a slightly different side effect profile. (Some centers also use it in the newly diagnosed IDH1 setting in combination with azacitidine.)

For IDH2-mutated AML specifically, enasidenib is the approved targeted option. Combination approaches pairing enasidenib with azacitidine or standard chemotherapy are under active clinical investigation.

IDH mutation not detected

A negative IDH result means neither IDH1 nor IDH2 mutations were found in the cells tested. Risk classification and treatment decisions will be guided by the other molecular findings — FLT3, NPM1, CEBPA, TP53, and the chromosome picture. A negative IDH result does not, by itself, indicate a more or less favorable prognosis; it simply means that IDH inhibitor drugs are not indicated based on IDH status.

As with other AML mutations, IDH status should be retested at relapse, since it can change.

Differentiation syndrome: an important side effect to know about

IDH inhibitors work by allowing leukemia cells to mature — a process called differentiation. In some patients, this happens rapidly, and a large number of maturing leukemia cells are suddenly released into the bloodstream. This flood of cells can trigger a serious reaction called differentiation syndrome.

Differentiation syndrome causes inflammation throughout the body. Symptoms can include fever, difficulty breathing, fluid buildup in the lungs or around the heart, low blood pressure, rapid weight gain due to fluid retention, and kidney injury. It can develop within days to weeks of starting an IDH inhibitor — or sometimes later in the course of treatment.

Differentiation syndrome can be life-threatening if it is not recognized and treated promptly. The treatment is a steroid called dexamethasone, which reduces inflammation. In severe cases, the IDH inhibitor may need to be temporarily stopped.

This side effect is not a sign that the drug is failing — in fact, it may indicate that the leukemia cells are responding and beginning to differentiate. But it does need urgent medical attention. If you are taking an IDH inhibitor and develop any of these symptoms — particularly new or worsening shortness of breath, fever, or unexplained weight gain — contact your medical team immediately. Do not wait for a scheduled appointment.

Your medical team will monitor you closely for differentiation syndrome, particularly during the first weeks of treatment. Knowing the warning signs and reporting them early are among the most important things you can do while on an IDH inhibitor.

IDH mutations in other blood cancers and solid tumors

IDH1 and IDH2 mutations are not unique to AML. They are also found in myelodysplastic syndromes (MDS), where they carry similar prognostic and treatment implications — ivosidenib is approved for IDH1-mutated MDS, and enasidenib has been studied in IDH2-mutated MDS. If you have MDS rather than AML and your report identifies an IDH mutation, your hematologist will explain whether IDH inhibitor therapy is appropriate in your situation.

IDH mutations are also found in certain solid tumors — most notably cholangiocarcinoma (a cancer of the bile ducts) and some brain tumors (gliomas). If you have encountered information about IDH inhibitors in the context of one of these cancers, the drugs used and the clinical context are different from those in AML, even though the underlying mutation affects the same genes.

What happens next

For patients newly diagnosed with IDH-mutated AML who are fit for intensive chemotherapy, standard induction chemotherapy is usually the first treatment, often with an IDH inhibitor added alongside it or used as maintenance therapy afterward. The specific approach depends on your overall risk classification — which takes into account IDH status together with all other molecular findings, chromosome results, and clinical features — and your overall health.

For patients who are not fit for intensive chemotherapy, the combination of an IDH inhibitor with azacitidine (a lower-intensity chemotherapy drug) is a standard first-line option for IDH1-mutated AML. A similar approach is used or under study for IDH2-mutated disease. Your hematologist will discuss which combination is appropriate based on your specific mutation type and health.

For patients with IDH-mutated AML that has relapsed or stopped responding to initial treatment, an IDH inhibitor is a core treatment option. Ivosidenib (for IDH1) or enasidenib (for IDH2) will typically be discussed, along with other salvage options and clinical trials.

After treatment begins, molecular testing for the IDH mutation will be repeated at regular intervals to assess how deeply the leukemia responds. Your hematologist will explain what each result means and how it influences ongoing treatment decisions, including whether stem cell transplantation is being considered.

If IDH testing has not yet been performed and you have been diagnosed with AML, it is worth asking when the molecular results will be available and how they will shape the treatment plan. IDH status should be known before the first treatment decision is made.

Questions to ask your doctor

Do I have an IDH1 mutation, an IDH2 mutation, or neither — and if positive, which specific mutation do I have?
What other mutations were found alongside the IDH mutation, and how do they together affect my risk classification?
Which IDH inhibitor is recommended for me, and will it be used alone or in combination with other treatments?
Am I being treated with intensive chemotherapy, or is a lower-intensity approach more appropriate for my situation?
What are the signs of differentiation syndrome, and what should I do if I develop them?
Will my IDH mutation be monitored over time to track treatment response and detect any remaining leukemia?
Is stem cell transplantation being considered for me, and how does my IDH result factor into that decision?
Are there clinical trials involving IDH-targeted treatments that I should know about?